scholarly journals Myosin with hypertrophic cardiac mutation R712L has a decreased working stroke which is rescued by omecamtiv mecarbil

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Aaron Snoberger ◽  
Bipasha Barua ◽  
Jennifer L Atherton ◽  
Henry Shuman ◽  
Eva Forgacs ◽  
...  
Keyword(s):  
Heart Failure ◽  
Atpase Activity ◽  
Binding Site ◽  
Single Molecule ◽  
Cardiac Failure ◽  
Flow Chamber ◽  
Severe Form ◽  
Gliding Motility ◽  
Cardiac Myosin ◽  
Omecamtiv Mecarbil

Hypertrophic cardiomyopathies (HCMs) are the leading cause of acute cardiac failure in young individuals. Over 300 mutations throughout β-cardiac myosin, including in the motor domain, are associated with HCM. A β-cardiac myosin motor mutation (R712L) leads to a severe form of HCM. Actin-gliding motility of R712L-myosin is inhibited, despite near-normal ATPase kinetics. By optical trapping, the working stroke of R712L-myosin was decreased 4-fold, but actin-attachment durations were normal. A prevalent hypothesis that HCM mutants are hypercontractile is thus not universal. R712 is adjacent to the binding site of the heart failure drug omecamtiv mecarbil (OM). OM suppresses the working stroke of normal β-cardiac myosin, but remarkably, OM rescues the R712L-myosin working stroke. Using a flow chamber to interrogate a single molecule during buffer exchange, we found OM rescue to be reversible. Thus, the R712L mutation uncouples lever arm rotation from ATPase activity and this inhibition is rescued by OM.

scholarly journals Human hypertrophic cardiomyopathy mutation R712L suppresses the working stroke of cardiac myosin and can be rescued by omecamtiv mecarbil

2020 ◽  
Author(s):  
Aaron Snoberger ◽  
Bipasha Barua ◽  
Jennifer L. Atherton ◽  
Henry Shuman ◽  
Eva Forgacs ◽  
...  
Keyword(s):  
Heart Failure ◽  
Hypertrophic Cardiomyopathy ◽  
Atpase Activity ◽  
Single Molecule ◽  
Cardiac Failure ◽  
Flow Chamber ◽  
Severe Form ◽  
Gliding Motility ◽  
Cardiac Myosin ◽  
Omecamtiv Mecarbil

AbstractHypertrophic cardiomyopathies (HCMs) are the leading cause of acute cardiac failure in young individuals. Over 300 mutations throughout β-cardiac myosin, including in the motor domain, are associated with HCM. A β-cardiac myosin motor mutation (R712L) leads to a severe form of HCM. Actin-gliding motility of R712L-myosin is inhibited, despite near normal ATPase kinetics. By optical trapping, the working stroke of R712L-myosin was decreased 4-fold, but actin-attachment durations were normal. A prevalent hypothesis that HCM mutants are hypercontractile is thus not universal. R712 is adjacent to the binding site of the heart failure drug omecamtiv mecarbil (OM). OM suppresses the working stroke of normal β-cardiac myosin, but remarkably, OM rescues the R712L-myosin working stroke. Using a flow chamber to interrogate a single molecule during buffer exchange, we found OM rescue to be reversible. Thus, the R712L mutation uncouples lever arm rotation from ATPase activity and this inhibition is rescued by OM.

scholarly journals Cardiac Myosin Activation with Omecamtiv Mecarbil in Systolic Heart Failure

2020 ◽  
Author(s):  
John R. Teerlink ◽  
Rafael Diaz ◽  
G. Michael Felker ◽  
John J.V. McMurray ◽  
Marco Metra ◽  
...  
Keyword(s):  
Heart Failure ◽  
Systolic Heart Failure ◽  
Cardiac Myosin ◽  
Omecamtiv Mecarbil

scholarly journals Heart failure drug changes the mechanoenzymology of the cardiac myosin powerstroke

2017 ◽  
Vol 114 (10) ◽  
pp. E1796-E1804 ◽  
Author(s):  
John A. Rohde ◽  
David D. Thomas ◽  
Joseph M. Muretta
Keyword(s):  
Heart Failure ◽  
Atp Hydrolysis ◽  
Cardiac Contractility ◽  
Cardiac Myosin ◽  
Transient Time ◽  
Time Resolved ◽  
Phosphate Release ◽  
Omecamtiv Mecarbil ◽  
Biochemical State ◽  
Kinetics Of

Omecamtiv mecarbil (OM), a putative heart failure therapeutic, increases cardiac contractility. We hypothesize that it does this by changing the structural kinetics of the myosin powerstroke. We tested this directly by performing transient time-resolved FRET on a ventricular cardiac myosin biosensor. Our results demonstrate that OM stabilizes myosin’s prepowerstroke structural state, supporting previous measurements showing that the drug shifts the equilibrium constant for myosin-catalyzed ATP hydrolysis toward the posthydrolysis biochemical state. OM slowed the actin-induced powerstroke, despite a twofold increase in the rate constant for actin-activated phosphate release, the biochemical step in myosin’s ATPase cycle associated with force generation and the conversion of chemical energy into mechanical work. We conclude that OM alters the energetics of cardiac myosin’s mechanical cycle, causing the powerstroke to occur after myosin weakly binds to actin and releases phosphate. We discuss the physiological implications for these changes.

Omecamtiv mecarbil: a new cardiac myosin activator for the treatment of heart failure

2015 ◽  
Vol 25 (1) ◽  
pp. 117-127 ◽  
Author(s):  
Licette CY Liu ◽  
Bernard Dorhout ◽  
Peter van der Meer ◽  
John R Teerlink ◽  
Adriaan A Voors
Keyword(s):  
Heart Failure ◽  
Cardiac Myosin ◽  
Omecamtiv Mecarbil

scholarly journals Stepwise nucleosome translocation by RSC remodeling complexes

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Bryan T Harada ◽  
William L Hwang ◽  
Sebastian Deindl ◽  
Nilanjana Chatterjee ◽  
Blaine Bartholomew ◽  
...  
Keyword(s):  
Free Energy ◽  
Atpase Activity ◽  
Binding Site ◽  
Single Molecule ◽  
Chromatin Structure ◽  
Atp Hydrolysis ◽  
Size Distributions ◽  
Dna Translocation ◽  
Step Size ◽  
Single Molecule Fret

The SWI/SNF-family remodelers regulate chromatin structure by coupling the free energy from ATP hydrolysis to the repositioning and restructuring of nucleosomes, but how the ATPase activity of these enzymes drives the motion of DNA across the nucleosome remains unclear. Here, we used single-molecule FRET to monitor the remodeling of mononucleosomes by the yeast SWI/SNF remodeler, RSC. We observed that RSC primarily translocates DNA around the nucleosome without substantial displacement of the H2A-H2B dimer. At the sites where DNA enters and exits the nucleosome, the DNA moves largely along or near its canonical wrapping path. The translocation of DNA occurs in a stepwise manner, and at both sites where DNA enters and exits the nucleosome, the step size distributions exhibit a peak at approximately 1–2 bp. These results suggest that the movement of DNA across the nucleosome is likely coupled directly to DNA translocation by the ATPase at its binding site inside the nucleosome.

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